bims-mecosi 2025-11-02 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–11–02
seven papers selected by
Verena Kohler, Umeå University

Potential Role of Membrane Contact Sites in the Dysregulation of the Crosstalk Between Mitochondria and Lysosomes in Alzheimer's Disease.
Mitochondria-associated endoplasmic reticulum membrane (MAM)-associated calpains system in preeclampsia.
Eliosin-an alternative product from the HmPKD1 locus is a component of endoplasmic reticulum mitochondria membrane contact sites.
Altered Expression of Calpastatin by Hypoxia Regulates Trophoblast Cell Function through Mitochondria Associated Endoplasmic Reticulum Membranes.
Targeting the mTOR-mitochondrial function axis: Calcitriol attenuates sarcopenic obesity with lipid dysregulation etiology.
ER morphological analysis associated with interstitial cells of Cajal and smooth muscle cells in the murine stomach.
Lysosome heterogeneity and diversity mapped through its distinct cellular functions.

Int J Mol Sci. 2025 Oct 10. pii: 9858. [Epub ahead of print]26(20):

Potential Role of Membrane Contact Sites in the Dysregulation of the Crosstalk Between Mitochondria and Lysosomes in Alzheimer's Disease.

Giulia Girolimetti, Matteo Calcagnile, Cecilia Bucci.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a gradual decline in cognitive abilities and a progressive loss of the neuronal system resulting from neuronal damage and death. The maintenance of neuronal homeostasis is intricately connected to the crosstalk and balance among organelles. Indeed, intracellular organelles are not just isolated compartments in the cell; instead, they are interdependent structures that can communicate through membrane contact sites (MCSs), forming physical connection points represented by proteinaceous tethers. Mitochondria and lysosomes have fundamental physiological functions within neurons, and accumulating evidence highlights their dysfunctions as AD features, strongly associated with the neurodegenerative process underlying the development and progression of AD. This review explores mitochondria-lysosome communication through MCSs, the tethering proteins and their functions in the cell, discussing the methodological challenges in measuring the structure and dynamics of contacts, and the potential role of altered mitochondria-lysosome communication in the context of organelle dysfunction related to neuron impairment in AD pathogenesis. The different abundance of the tethering proteins was considered in healthy physiological and in AD-related conditions to assess the possible organelle communication dysregulation and the subsequent cellular function alterations, and to evaluate the role of mitochondria-lysosome MCSs in the pathogenesis of this disorder.

Keywords:  Alzheimer’s disease; lysosomes; membrane contact site; mitochondria

DOI:  https://doi.org/10.3390/ijms26209858
BMC Pregnancy Childbirth. 2025 Oct 25. 25(1): 1133

Mitochondria-associated endoplasmic reticulum membrane (MAM)-associated calpains system in preeclampsia.

Cui Zhang, Jingjing Jiang, Hongfang Kong, Xuyuan Ma, Hong Xin.

   BACKGROUND: Preeclampsia (PE) is a multisystem disorder characterized primarily by hypertension and proteinuria after 20 weeks of gestation, significantly impacting maternal and fetal health. The etiology remains unclear, but it is primarily attributed to placental dysfunction leading to systemic vascular endothelial damage and inflammatory responses. Mitochondria-associated endoplasmic reticulum membranes (MAMs) influence mitochondrial and endoplasmic reticulum (ER) function by regulating calcium homeostasis, autophagy, and apoptosis. In PE, mitochondrial dysfunction and ER stress have been widely observed. However, detailed investigations into the specific mechanisms and roles of MAMs in PE remain limited. Thus, this study aimed to investigate how MAM-associated biomarkers affect PE.
METHODS: The study involved 31 women with early-onset PE, 30 with late-onset PE, and 54 healthy controls matched for gestational age. Placental morphology and MAM structure in both PE and control tissues were assessed using Hematoxylin-Eosin (HE) staining and electron microscopy (EM). Bioinformatics analysis of Gene Expression Omnibus (GEO) datasets (GSE190971, GSE24129) identified MAMs-related genes (MAMs-RGs) and candidate biomarkers through weighted gene co-expression network analysis (WGCNA), machine learning algorithms (Least absolute shrinkage and selection operator, Support Vector Machine Recursive Feature Elimination), and functional enrichment. Real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to validate biomarker expression in PE placentas. Calpain-1, calpain-2, and calpastatin expression levels were evaluated using Immunofluorescence and Western blotting techniques.
RESULTS: The results showed early-onset PE (EOPE) had higher abnormal pregnancy history, fetal growth restriction, systolic/diastolic ratio, and lower placental growth factor than late-onset PE (LOPE) and controls. Both PE types had fewer placental villi, but EOPE showed more severe ultrastructural changes in mitochondria-associated membranes. Bioinformatics identified CAST as potential MAM biomarkers, and its expression was significantly downregulated in PE samples (P < 0.01). Immunofluorescence and Western blotting showed calpain-1 and calpastatin were decreased in EOPE, while calpain-2 was reduced in both PE types, with calpain-1 increased in LOPE.
CONCLUSIONS: EOPE is characterized by placental dysfunction, with increased MAM contact observed in PE placentas.The calpain-calpastatin system may be involved in placental dysfunction in PE, with calpain-2 downregulation observed in both PE subtypes and calpain-1 dysregulation differing between EOPE and LOPE. These changes are accompanied by increased MAM contacts in PE placentas, suggesting a potential link between MAM structural abnormalities and calpain system dysregulation, with calpain-2 levels potentially associated with disease severity.

Keywords:  Biomarkers; Calpains; Calpastatin; Electron microscopy; Mitochondria-associated membranes; Preeclampsia

DOI:  https://doi.org/10.1186/s12884-025-08244-1
PLoS One. 2025 ;20(10): e0332969

Eliosin-an alternative product from the HmPKD1 locus is a component of endoplasmic reticulum mitochondria membrane contact sites.

Almira Kurbegovic, Virginie Lazar, Wei-Min Xu, Maya Seshan, John S Underwood, Radmila Micanovic, Jeremy M Pomerantz, Rajneesh Srivastava, Sarath Janga, Emma H Doud, Sherry Clendenon, Marie Trudel, Angela Wandinger-Ness, Robert L Bacallao.

The human PKD1 gene locus region is the site that when mutated, causes 87% of the cases of human autosomal dominant polycystic kidney disease (ADPKD). This gene generates a full-length 14 kb message and encodes polycystin-1 (PC1). Informatic analysis of the PKD1 locus reveals 38 additional transcripts in the database, the most abundant cDNA is TESTI2047494 (GenBank ACC. No. DB056008) that maps to the 3' region with active and open chromatin. This PKD1 locus region in human adult kidney cDNA probed by several sets of primers and sequencing produces an alternative transcript with a transcriptional start site in intron 40 that undergoes exon 42 skipping but aligns with exon 43-46 conventional splicing of the HmPKD1 gene. To assess the broader significance of this transcript, transcriptional characterization uncovered a highly similar murine renal alternative transcript suggesting a conserved functional role. The human alternative cDNA was analyzed for protein expression and only one of three reading frames led to a 47 kDa protein that is given the name Eliosin. Eliosin protein initiates from a non-canonical translation start site Leucine in exon 41 that generates 5 unique amino-terminal amino acids in a different frame from PKD1. In 2D-gel analysis, Eliosin protein detected by anti-C terminal PC1 antibodies has a pI of 9.0 and the relative molecular weight was confirmed. Eliosin co-localizes with mitofusin-1, IP3R and dynamin related protein-1 (DRP1), proteins associated with ER mitochondria membrane contact sites (ERMCS). Eliosin observed in cotransfection studies with DRP1 support sequestration and/or competition mechanism at the ERMCS from classical interaction. Strikingly, exogenous Eliosin in immortalized ADPKD renal epithelial cells converts fragmented mitochondria populations to a filamentous shape. Our studies highlight the genomic complexity of the locus, a newly identified transcript and ERMCS protein, Eliosin with a role in mitochondria dynamics and potential impact in ADPKD progression.

DOI: https://doi.org/10.1371/journal.pone.0332969
Reprod Sci. 2025 Oct 29.

Altered Expression of Calpastatin by Hypoxia Regulates Trophoblast Cell Function through Mitochondria Associated Endoplasmic Reticulum Membranes.

Cui Zhang, Jingjing Jiang, Hongfang Kong, Xuyuan Ma, Haiyan Li, Hong Xin.

  Preeclampsia (PE), a severe pregnancy complication, arises from placental hypoxia-induced mitochondrial and endoplasmic reticulum (ER) oxidative stress, contributing to inadequate spiral artery remodeling and endothelial dysfunction. Calpastatin, a mitochondrial protective protein, mitigates oxidative stress-related pathologies, but its role in PE remains unclear. This study investigated the effects of Calpastatin on trophoblast cellular proliferation, migration, invasion, apoptosis, and the expression of autophagy protein (PINK1), mitochondrial dynamics protein (Mfn2), ER stress protein (GRP78), ATP, Ca2+, and mitochondrial membrane potential under hypoxia using transfected HTR8-SVneo cells. Calpastatin overexpression significantly enhanced proliferation, migration, and invasion while reducing apoptosis (P < 0.05); knockdown inversely affected these parameters under normoxic conditions. Under hypoxia, overexpression further amplified proliferation and migration (P < 0.01), whereas knockdown reduced migration at 48 h (P = 0.04) but not proliferation. Invasion decreased and apoptosis increased in both groups (P < 0.05). Calpastatin overexpression upregulated PINK1, downregulated Mfn2/GRP78, increased ATP and mitochondrial membrane potential, and reduced Ca2+. Conversely, knockdown suppressed Pink1/Parkin, elevated Mfn2/Drp1/GRP78, decreased ATP, and increased Ca2+ and mitochondrial depolarization (P < 0.05). These findings demonstrate calpastatin promotes trophoblast function by maintaining mitochondrial-ER contact sites stability and ATP production, Ca2+ homeostasis, and mitophagy mechanism, suggesting its critical role in PE pathogenesis.

Keywords:  Endoplasmic reticulum; Mitochondria; Oxidative stress; Preeclampsia; Trophoblasts

DOI:  https://doi.org/10.1007/s43032-025-01995-4
Free Radic Biol Med. 2025 Oct 29. pii: S0891-5849(25)01307-3. [Epub ahead of print]

Targeting the mTOR-mitochondrial function axis: Calcitriol attenuates sarcopenic obesity with lipid dysregulation etiology.

Shangheng Fan, Youbo Yu, Yunqin Wei, Jing An, Qi Wang, Yan Yang.

  Sarcopenic obesity (SO) manifests as intramuscular lipid deposition and regenerative impairment triggered by dysregulation of the mitophagy-associated axis. Mitochondria-associated membranes (MAMs) are critical for lipid metabolism and mitochondrial function regulation. The mechanistic target of rapamycin (mTOR) is a functional protein at the MAMs and a central metabolic regulator; however, the underlying mechanisms by which mTOR dysregulation affects SO remain unclear. Calcitriol possesses the potential to improve mitochondrial function and fatty acid oxidation. This study investigated the mechanism of Calcitriol in SO using an in vivo SO mice model and an in vitro lipotoxicity-induced myoblast atrophy model. Calcitriol significantly ameliorated muscle atrophy in SO mice, as evidenced by increased grip strength, enhanced behavioral activity, and improved histopathological lesions. Untargeted metabolomic analysis revealed that Calcitriol intervention significantly ameliorated lipid metabolic disorders in SO mice, manifested by a marked reversal of aberrant changes in key lipid metabolites and the restoration of β-oxidation and mitochondrial function-related metabolites to physiological levels. Calcitriol treatment reduced pro-inflammatory cytokines while increasing anti-inflammatory cytokines, restored the contact distance between mitochondria and endoplasmic reticulum at MAMs, and enhanced mitophagy. RNA-Seq, molecular docking, and molecular dynamics simulations collectively demonstrated that these effects were attributable to mTOR downregulation. Furthermore, in vitro mTOR knockdown confirmed that Calcitriol ameliorates lipotoxicity-induced myoblast atrophy through an mTOR-dependent pathway, maintaining MAMs, stabilizing calcium homeostasis, mitigating mitochondrial dysfunction, and reducing ROS generation. In summary, this study demonstrates a novel mechanism whereby Calcitriol effectively inhibits mTOR, which is associated with the restoration of structural integrity of MAMs and the amelioration of disordered lipid metabolism, thereby attenuating SO.

Keywords:  Calcitriol; Lipid metabolic reprogramming; Mitochondria-associated endoplasmic reticulum membranes; Sarcopenic obesity; mTOR

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.282
Cell Tissue Res. 2025 Oct 28.

ER morphological analysis associated with interstitial cells of Cajal and smooth muscle cells in the murine stomach.

Hiromi Tamada, Satoshi Iino.

  In the gastrointestinal tract, several modulators are involved in generating complex motility patterns, including smooth muscle cells (SMCs), interstitial cells of Cajal (ICCs), and PDGFRα+ cells. Notably, ICCs are excitable cells that generate characteristic oscillations in pacemaker activity mediated by the cytoplasmic Ca2+ concentration. Since the primary source of cytoplasmic Ca2+ is the endoplasmic reticulum (ER) or sarcoplasmic reticulum (SR), its distribution and localisation in the cytoplasm may indicate characteristic aspects that help in understanding its physiological functions. Furthermore, caveolae, which are invaginations of the plasma membrane (PM) observed in both ICCs and SMCs, are key sites for Ca2+ sparks, and their functions have been well studied in muscle cells. However, the mechanism by which caveolae and ER interact to regulate Ca2+ in ICCs remains unclear compared with that in SMCs. In this study, microdomains comprising the PM, caveolae, and ER/SR were analysed using focused ion beam/scanning electron microscopy (FIB/SEM) to provide new insights into ICC functional analysis. Additionally, as mitochondria could regulate local Ca2+ concentration, mitochondria-associated membrane (MAM) contacts with the ER were also analysed in ICCs. Novel ER ultrastructures with distinct characteristics and distributions were identified in each cell type by FIB/SEM. Furthermore, reconstructed three-dimensional (3D) images enabled measurement of the distance between the PM and ER, as well as the MAM areas, thus contributing to a better understanding of ICC physiological features. These new morphological insights may help resolve controversial interpretations in physiological and pharmacological studies of ICCs.

Keywords:  Endoplasmic reticulum; Focused ion beam/scanning electron microscopy; Interstitial cells of Cajal; Plasma membrane

DOI:  https://doi.org/10.1007/s00441-025-04016-7
Cell Mol Life Sci. 2025 Oct 30. 82(1): 380

Lysosome heterogeneity and diversity mapped through its distinct cellular functions.

Indira Chavan, Arindam Bhattacharjee.

  Lysosomes respond to cellular nutrient availability and diverse oncoming vesicle traffic such as endocytosis and autophagy by switching between anabolic signaling or catabolic hydrolase activity, which coincides with a drastic shift in their cellular distribution, organelle contacts, ion homeostasis, membrane proteome and lipidome. Emerging evidence now reveals a dynamic remodeling of lysosomal membrane to counter membrane damage, acting via extensive lipid transfer from the endoplasmic reticulum or by localized membrane repair. Functionally, lysosomes play a key role in lipid metabolism and intracellular calcium signaling. Unsurprisingly, disease-associated lysosomes are either often hyperactive- thus promoting abnormal tissue growth, or hypoactive, promoting storage. Taken together, this presents an incredible functional diversity among the cellular population of lysosomes. Here, we discuss this intracellular heterogeneity and intercellular diversity in context of lysosomal function in health and disease.

Keywords:  Lipid storage disorders; Lysosome plasticity; Lysosome quality control; Lysosome subpopulations; Phosphoinositides

DOI:  https://doi.org/10.1007/s00018-025-05883-7